The long-term goal of the PI is to examine the effects of aging and heart failure (HF) on the exercise pressor reflex. This reflex is a major determinant of blood flow and blood pressure (BP) control during exercise. The general goals for Project 1 will be to examine the role ATP plays in evoking the exercise pressor reflex in human subjects. This goal is based on recent animal work suggesting that ATP plays a crucial role in stimulating muscle afferents and evoking this reflex. A second goal will be to examine why vasoconstrictor mechanisms are accentuated in HF. The specific aims of this project are: 1) To determine the effects of ATP infusions into the arterial supply of the quadriceps femoris muscle. We hypothesize that femoral artery infusions of ATP will evoke an increase in muscle sympathetic nerve activity (MSNA). We further postulate that ATP will sensitize muscle afferents and increase MSNA during muscle compression. Finally, we postulate that Vitamin B6, a P2 receptor blocker will attenuate the MSNA response; 2) To measure interstitial ATP using microdialysis during intermittent static quadriceps femoris muscle contractions. We hypothesize that as compared to normal controls, the MSNA response will be increased in HF, and reduced in aged subjects. These relative differences in MSNA responses will be associated with proportional differences in interstitial ATP; 3). We have shown that muscle reflex engagement in HF evokes greater vasoconstriction than is seen in normal subjects. In this proposal we will examine vasoconstrictor responses in contracting muscle in HF subjects and controls. We hypothesize that the enhanced vasoconstrictor responses seen in HF are due to increased interstitial norepinephrine (NE) levels and not to reduced counterbalancing dilator influences or to differences in alpha 1 or alpha 2 adrenergic responsiveness; 4) Using Doppler methods, we have shown that the mechanoreflex is the major determinant of renal vasoconstriction during muscle contraction. In this proposal we will expand these efforts to the study of HF. We hypothesize that renal vasoconstriction will be greater in HF subjects. In this proposal a large amount of published and pilot data will be presented demonstrating that the studies are feasible, conceptually sound and flow logically from prior findings from this laboratory. The proposed studies will utilize a number of state-of-the-art methodologies including microneurography (sympathetic nerve traffic), microdialysis (interstitial ATP and NE), Doppler ultrasound (renal and peripheral arterial blood flow velocity) and intra-arterial infusions. These studies will be performed in Core Laboratory B.